Osteoarthritis afflicts over 50 million individuals in the developed world and this number is expected to rise as median age and life expectancy increase. The economic impact of osteoarthritis treatment exceeds $30 billion annually in the United States alone. The financial burden, as well as other factors (i.e., quality of life, loss of labor hours, etc.) incentivizes development of more effective treatments.
Current treatments for osteoarthritis (OA) include non-steroidal anti-inflammatories [Scott et al. (2000) Rheumatol. 39:1095-101], intra-articular corticosteroid injections [Arroll et al. (2004) BMJ 2004; 328:8693], and chondroitin sulfate or glucosamine supplements [Sinusas (2012) Am. Fam. Physician 85:49-56]; however, they have little or no effect on disease progression. A more recent approach to the treatment of OA is the intra-articular injection of the natural synovial fluid glycosaminoglycan, hyaluronic acid (HA) [Mabuchi et al. (1994) J. Biomed. Mat. Res. 28:865-70]. HA increases synovial fluid viscosity (e.g., viscosupplementation) to reduce the coefficient of friction in the hydrodynamic mode of lubrication [Tadmor et al. (2002) J. Biomed. Mat. Res. 61:514-23]. The other predominant lubrication component in synovial fluid is lubricin, a high molecular weight glycoprotein that reduces the coefficient of friction in the boundary mode of lubrication [Swann et al. (1972) J. Biol. Chem. 247:8069-73; Jay et al. (1998) J. Biomed. Mat. Res. 40:414-8; Chawla et al. (2013) Acta Biomat. 6:3388-94]. As the field of articular cartilage lubrication matures, it appears that both the hydrodynamic and boundary modes of lubrication are needed to prevent disease progression in weight-bearing joints such as the knee [Das et al. (2013) Biomacromol. 14:1669-77].
In damaged cartilage, chondrocyte production of lubricin is compromised and boundary mode lubrication is reduced [Elsaid et al. (2012) Osteoarthritis Cartilage 20:940-948]. Intra-articular injection of supplemental lubricin, as well as the truncated recombinant lubricin construct LUB:1, slows progression of OA in rat models of disease [Jay et al. (2010) Arthritis Rheum. 62:2382-91; Flannery et al. (2009) Arthritis Rheum. 60:840-7]. However, to date, the large-scale recombinant manufacture of both lubricin and LUB:1 remains challenging owing to multiple amino acid repeats in the protein core, as well as the high degree of glycosylation [Jay (2004) Curr. Opin. Orthop. 15:355-359; Jones et al. (2007) J. Orthop. Res. 25:283-292].
Nature's natural lubricants, such as proteoglycan aggregates and mucins (e.g., lubricin) keep natural surfaces hydrophilic. However, to date, the large-scale recombinant manufacture of both lubricin and LUB:1 remains challenging owing to multiple amino acid repeats in the protein core, as well as the high degree of glycosylation [Jay (2004) Curr. Opin. Orthop. 15:355-359; Jones et al. (2007) J. Orthop. Res. 25:283-292]. Consequently a biomimetic for lubricin and LUB:1 capable of providing boundary lubrication is needed.
Lubricating graft another polymers are known in the art but none of these brush copolymers reported as boundary lubricants for articular joints. For example, Müller describes poly(L-lysine)-graft-poly(ethylene glycol) (pLL-g-PEG), a polycationic polymer capable of adsorbing to and lubricating negatively-charged surfaces [Müller (2009) “Aqueous Lubrication by Means of Surface-Bound Brush-Like Copolymers” Doctoral Dissertation ETH No. 16030]. Perrino (2009) reports to pLL-g-dextran as another brush-forming polymer that promotes lubricity of negatively charged surfaces [Perrino (2009) Poly(L-lysine)-g-dextran (pLL-g-dex): Brush-forming, Biomimetic Carbohydrate Chains that Inhibit Fouling and Promote Lubricity” Doctoral Dissertation ETH No. 18224]. Spiller reviews the use of hydrogels for repairing cartilage defects, including natural polymers (e.g., alginate, collagen, fibrin, and hyaluronan) and synthetic polymers (e.g., PVA, PEG and modified PEGs) but does not include any hydrogels that are graft brush copolymers [Spiller et al. (2011) Tissue Eng. 17:281-299].
A poly(acrylic acid)-graft-poly(ethylene glycol) (pAA-g-PEG) was investigated to determine the frictional forced during a sliding interactions between a silicone skin coated with a PAA-g-PEG polymer and artificial grass in the presence and absence of water. Under dry conditions, the coefficient of friction is greater than 1 and under wet conditions, the value is below 0.01 at low sliding velocities [Van der Heide et al. (2009) Friction 1:130-142].
Hartung describes the lubrication of ceramics using brush-forming graft copolymers, including poly(allylamine)-g-PEG and pAA-g-PEG copolymers. These pAA-g-PEG copolymers lowered the coefficient of fraction for sapphire matched tribopairs but not for ZrO2 matched tribopairs. In that study, the pAA-g-PEG polymers had a moderately long backbone (15 kDa), a graft ratio of 3-6 and 5 kDa PEG side chains [Hartung (2009) “Aqueous Lubrication of Ceramics by means of Brush-forming Graft Copolymers” Doctoral Dissertation ETH No. 18428]. Doménech (2006) reports pAA-g-PEG graft copolymers as mucoadhesive delivery systems using 1 kDa and 2 kDa PEG side chains (at varying ratios) [Doménech et al. (2006) Eur. J. Pharm. Biopharm. 63:11-8]. Sun reported the use of pAA-g-PEG micelles to encapsulate and deliver an anti-cancer drug [Sun et al. (2013) Biomaterials 34:6818-28].